A complex interaction of different processes play a critical role in the development of hematopoietic lineages, and dysfunction of these interactions are directly involved in the pathogenesis of many types of human leukemia. The overall goal of this program is to study how these interacting factors direct normal hematopoiesis, and how abnormalities lead to leukemias. We will specifically focus on important hematopoietic transcription factors, fusion peptides found in leukemias as a result of translocations, the signaling pathways which affect these proteins, and their effect on alteration of defined hematopoietic precursor subsets. The future aims are to use this knowledge to design specific therapies for treatment of hematopoietic malignancies. The specific projects will include the following proposals: (1) C/EBP alpha signaling and regulation in myelopoiesis and leukemia; (2) C/EBP alpha and PU.1 in Normal and Malignant Hematopoiesis; (3) RUNX1 in Myeloid Development; and (4) The role of JNK signaling pathways in leukemia. The administrative core shall be responsible for many interactive functions of the program, including regular meetings, seminars, and communication among projects. By combining a variety of approaches, including studies of transcriptional regulation, protein-protein interactions, phosphorylation and signal transduction, knockout and knock-in mice, and structure-function relationships, we will provide new information concerning a very interesting group of proteins whose functions and interactions are directly related to hematopoiesis and leukemogenesis.